Quality control of substrate coatings

ABSTRACT

The present invention relates to devices and methods for detecting the amount (degree, extent) of material coating a medical device or substrate, in particular the present invention relates to devices and methods for detecting the amount of vaccine material coating a microarray patch.

FIELD OF THE INVENTION

The present invention relates to devices and methods for detecting theamount of material coating a medical device or substrate, in particularthe present invention relates to devices and methods for detecting theamount of vaccine material coating a microarray patch.

BACKGROUND OF THE INVENTION

Medical devices may be coated with any number of biocompatiblematerials. Therapeutic drugs, agents or compounds may be mixed with thebiocompatible materials and affixed to at least a portion of the medicaldevice. These therapeutic drugs, agents or compounds may be utilized topromote healing deliver drugs and provide pain relief. Various materialsand coating methodologies may be utilized to maintain the drugs, agentsor compounds on the medical device until delivered and positioned.Medical devices that may be coated with various compounds includestents, grafts, anastomotic devices, perivascular wraps, sutures,staples and microprojection arrays. Microprojection arrays or microarray patches (MAPS) are an effective way of delivering therapeuticagents or biomarkers to patients as the patches induce minimal or nopain, induce little or no injury from the microneedles and reduce thepossibility of cross infection. The solid projections or needles on apatch can be coated with drugs or macromolecules. These can besubsequently delivered to a desired target by the penetration of theprojections or needles into the skin. The microprojections can be coatedby the therapeutic agents using a variety of techniques such as dipcoating, spray coating, gas jet drying, electrodynamic atomization andink jet printing.

Regardless of the methods used for coating the microprojections on thearrays it is useful to assess the amount of material coating the targetdelivery region of the microprojections which is often the upper ½ to ¼of the microprojections. Several different techniques have been appliedin an attempt to quantify the amount of material coated onto themicroprojections. One technique provides for dissolving the coating andquantifying the active material by high-performance liquidchromatography (Ma, et al. J. Pharm Sci. 2014 103(11): 3621-3630. Othertechniques to determine the loading of material onto microprojectionarrays include determining the residual amount of material either on themicroprojections after use or on the skin after the microprojectionarray has been removed. Fluorescence microscopy can detect fluorescentmaterials on the microprojections or in the skin after themicroprojection array has been removed. Scanning electron microscopy canbe used to take images of the microprojections before and after coating.These techniques usually require destruction of the coating and/or arecumbersome and slow. There exists a need to assess each microprojectionarray at high speed in an aseptic manufacturing environment to determinethat the dose and position of the coated material, such as a vaccine, onthe projections is correct. Preferably, the method for assessing thedose and position of the coated material would not destroy the coatingin the process.

As the dried vaccine on the microprojections appears optically “clear”,the use of standard imaging techniques to establish contrast between thecoating and the polymer is not straightforward. Furthermore, it isdesirable to determine if the upper portions of the microprojections arecoated as this is the portion of the microprojection that enters theskin to deliver the material to the subject. Coating of the lowerportions of the microprojections and/or the base upon which themicroprojections rest is a waste of valuable biological material. Thedetermination of the loading of the coating should be performed in anaseptic, non-destructive and rapid fashion.

The reference in this specification to any prior publication (orinformation derived from it), or to any matter which is known, is not,and should not be taken as an acknowledgment or admission or any form ofsuggestion that the prior publication (or information derived from it)or known matter forms part of the common general knowledge in the fieldof endeavor to which this specification relates.

SUMMARY OF THE INVENTION

The present invention relates to devices and methods for detecting theamount of material coating a medical device or substrate. In particular,the devices and methods of the present invention are able to detect theamount of vaccine material coating a microarray patch. Uncoatedsubstrate surfaces (e.g. polymers) may have different reflectance and/ora fluorescence emission spectrum from a coated substrate when thesubstrate is irradiated with a radiation source. Often, the reflectanceor fluorescence signal is reduced when the substrate is coated versusthe uncoated substrate.

The devices and methods of the present invention enable the use ofelectromagnetic radiation directed onto an uncoated/coatedmicroprojection array or micro array patch (MAP) to be reflected off thearray or to induce an electromagnetic emission and detected to determinethe extent of coating of the microprojections on the microprojectionarrays. The use of a laser (or other illumination source withappropriate illumination filters), and an intensity sensor (withappropriately chosen collection filters) to measure the reflected oremitted intensity of the electromagnetic radiation from a coated MAPcorrelates with coating performance or transfer efficiency of thecoating onto the microprojections.

Inkjet coating is an emerging technology that can aseptically coatbiologics onto MAP's. High speed reflectance measurement(s) allows aquantifiable value to ascertain whether the coating on the projectionmeets specification in terms of the mass of coated material and itsposition on the patch relative to base.

In one broad form, an aspect of the present invention seeks to provide amethod for determining the amount (degree, extent) of coating onmicroprojections of a coated microprojection array, the methodcomprising: irradiating an uncoated microprojection array with anelectromagnetic radiation source; measuring the reflected radiation fromthe uncoated microprojection array; irradiating an uncoatedmicroprojection array with an electromagnetic radiation source;measuring the reflected radiation from the uncoated microprojectionarray; and determining the extent of coating on the microprojections bycomparing the reflected radiation from the uncoated microprojectionarray to that of the coated microprojection array.

In one embodiment, the measuring of the reflected radiation from theuncoated microprojection array and the measuring of the reflectedradiation from the coated microprojection array is done simultaneously.

In one embodiment, the measuring of the reflected radiation from theuncoated microprojection array and the measuring of the reflectedradiation from the coated microprojection array is done sequentially.

In another broad form, an aspect of the present invention seeks toprovide a method for determining the amount of coating on themicroprojections of a coated microprojection array, the microprojectionarray comprising a base from which the microprojections project, themethod comprising: irradiating the coated microprojection array with alight source; measuring the reflected radiation from the base of thecoated microprojection array; and determining the amount of coating onthe microprojections by comparing the reflected radiation from thecoated microprojection array to that of an uncoated microprojectionarray.

In one embodiment, the reflected radiation is measured by a sensor.

In one embodiment, the number of sensors is four.

In one embodiment, the sensors are at approximately 45 degree downwardangle to the microprojections and at 45 degrees out of alignment withthe rows of microprojections.

In one embodiment, the electromagnetic radiation source is substantiallyperpendicular to the microprojection array.

In one embodiment, the electromagnetic radiation source is at an anglerelative to the microprojection array.

In one embodiment, the electromagnetic radiation source is aligned overthe microprojection array such that the angle relative to themicroprojections is less than 5°.

In one embodiment, the electromagnetic radiation source is aligned overthe microprojection array such that the angle relative to themicroprojections is less than about 20°.

In one embodiment, the electromagnetic radiation source is aligned overthe microprojection array such that the angle relative to themicroprojections is less than about 45°.

In another broad form, an aspect of the present invention seeks toprovide a device for measuring the coating on the microprojections on amicroprojection array, the device comprising: an electromagneticradiation source for illuminating the microprojection array; amicroprojection array housing for mounting the microprojection array;and one or more sensors for detecting reflected radiation from themicroprojection array.

In one embodiment, the radiation source is a laser diode.

In one embodiment, the radiation source is a laser diode which emitsradiation from about 200 nm to 10000 nm.

In one embodiment, the radiation source is a laser diode which emitsradiation at 635 nm.

In one embodiment, the sensor is a silicon photodiode.

In one embodiment, the silicon photodiode has a detection range of 200to 1100 nm.

In one embodiment, the device is confined in an aseptic housing.

In one embodiment, the device further comprises a reference sensor.

In one embodiment, the number of sensors is four.

In one embodiment, the sensors are at approximately 45 degree downwardangle to the microprojections and at 45 degrees out of alignment withthe rows of microprojections.

In one embodiment, the electromagnetic radiation source is substantiallyperpendicular to the microprojection array.

In one embodiment, the electromagnetic radiation source is aligned overthe microprojection array such that the angle relative to themicroprojections is less than 5°.

In another broad form, an aspect of the present invention seeks toprovide a device for measuring the coating on the microprojections on amicroprojection array, the device comprising: a laser diode forilluminating the microprojection array; an aspheric lens; a beam shapingdiffuser; a focusing lens wherein the aspheric lens is positionedbetween the laser diode and the beam shaping diffuser and the beamshaping diffuser is positioned between the aspheric lens and thefocusing lens and the focusing lens is positioned between the beamshaping filter and the microprojection array housing; microprojectionarray housing for mounting a microprojection array; a bi-convex lens; asensor for detecting reflected light from the microprojection arraywherein the biconvex lens is positioned between the microprojectionarray housing and the receiver; and a power meter connected to thesensor.

In one embodiment, the device further comprises a microarray mountingstation.

In one embodiment, the device further comprises one or more microarrays.

In one embodiment, the laser diode emits electromagnetic radiation atbout 635 nm.

In one embodiment, the device further comprises an aperture positionedbetween the focusing lens and the microprojection array housing.

In one embodiment, the device further comprises a mirror positionedbetween the aperture and the microprojection array housing

In one embodiment, the device further comprises a reference sensor.

In one embodiment, the number of sensors is four.

In one embodiment, the sensors are at approximately 45 degree downwardangle to the microprojections and at 45 degrees out of alignment withthe rows of microprojections.

In one embodiment, the laser diode is substantially perpendicular to themicroprojection array.

In one embodiment, the laser diode is aligned over the microprojectionarray such that the angle relative to the microprojections is less than5°.

In another broad form, an aspect of the present invention seeks toprovide a method for determining the extent (degree, amount) of coatingon microprojections of a coated microprojection array comprising:irradiating an uncoated microprojection array with an electromagneticradiation source; measuring the emitted radiation from the uncoatedmicroprojection array; irradiating a coated microprojection array with alight source; measuring the emitted radiation from the coatedmicroprojection array; and determining the extent of coating on themicroprojections by comparing the emitted radiation from the uncoatedmicroprojection array to that of the coated microprojection array.

In one embodiment, the emitted radiation is fluorescence.

In one embodiment, the electromagnetic radiation source emits atapproximately 445 nm.

In one embodiment, the fluorescence is detected by a sensor with afilter having a bandpass of between about 455 nm to 515 nm.

In another broad form, an aspect of the present invention seeks toprovide a method for determining the extent (degree, amount) of coatingon a substrate comprising: irradiating an uncoated microprojection arraywith a first electromagnetic radiation source which reflects off thesubstrate and a second electromagnetic radiation source which promotesfluorescence in either the substrate or the coating or both; measuringthe reflected radiation from the uncoated microprojection array;measuring the emitted fluorescence radiation from the uncoatedmicroprojection array; irradiating a coated microprojection array with afirst electromagnetic radiation source which reflects off the substrateand a second electromagnetic radiation source which promotesfluorescence in either the substrate or the coating or both irradiatinga coated microprojection array with a light source; measuring thereflected radiation from the coated microprojection array; measuring theemitted fluorescence radiation from the coated microprojection array;and determining the extent of coating on the microprojections bycomparing the reflected radiation from the uncoated microprojectionarray to that of the coated microprojection array and by comparing thereflected radiation from the uncoated microprojection array to that ofthe coated microprojection array.

In another broad form, an aspect of the present invention seeks toprovide a method for controlling the quality of coated microprojectionarrays, the method including: determining the amount (degree, extent) ofcoating on microprojections of a coated microprojection array using themethod as described above; comparing the determined amount of coating toa coating specification; and rejecting the coated microprojection arrayif the determined amount of coating is outside of the coatingspecification.

In another broad form, an aspect of the present invention seeks toprovide a system for controlling the quality of coated microprojectionarrays, the system including a device as described above that determinesthe amount of coating on microprojections of a coated microprojectionarray; and a processing system configured to: receive, from the device,an indication of the determined amount of coating; compare thedetermined amount of coating to a coating specification; and determinethat the coated microprojection array should be rejected if thedetermined amount of coating is outside of the coating specification.

It will be appreciated that the broad forms of the invention and theirrespective features can be used in conjunction, interchangeably and/orindependently, and reference to separate broad forms is not intended tobe limiting.

BRIEF DESCRIPTION OF THE DRAWINGS

Various examples and embodiments of the present invention will now bedescribed with reference to the accompanying drawings, in which:

FIG. 1A is a schematic diagram of a side view of the microprojectionarray and the relative position of the detector and illumination sourcerelative to the microprojection array; FIG. 1B is the image the detectorwould see given the orientation of the detector in accordance with FIG.1A.

FIG. 2A is a schematic diagram of a side view of the microprojectionarray and the relative position of the detector at a 45 degree angle tothe microprojection array; FIG. 2B is a schematic diagram of an overheadview of the detector direction relative to the microprojection array andthe direction of the detector for detecting reflectance; FIG. 2C is theimage the detector would see given the orientation of the detector inaccordance with FIGS. 2A and 2B; FIG. 2D is a schematic diagram of aside view of the microprojection array and the relative position of thedetector at a 45 degree angle to the microprojection array; FIG. 2E is aschematic diagram of an overhead view of the detector direction relativeto the microprojection array and the direction of the detector fordetecting reflectance; FIG. 2F is the image the detector would see giventhe orientation of the detector in accordance with FIGS. 2D and 2E; FIG.3 is a schematic diagram of an overhead view of a microprojection arraywhere the radiation illumination is from the top with little or no angleand the use of four detectors at approximately 45 degree downward angleand at 45 degrees out of alignment with the rows of microprojections.

FIGS. 4A-4D are schematic diagrams of an illumination schemerespectively, large spot reflectance, linear dot array, line scan arrayand two dimensional array.

FIG. 5A is a fluorescence image of dried vaccine on a flat polymer disc,to demonstrate the principle of fluorescence reduction. The excitationwavelength is set at 445 nm and the emission filter is 455-530 nm. Thepolymer surface fluoresces when excited with 445 nm light, and the driedvaccine reduces the measured intensity; FIG. 5B is a photograph of apolymer microprojection array coated with dried vaccine where theexcitation wavelength is set at 405 nm and the emission filter is495-515 nm. In this scenario, the dried vaccine does not appear tosignificantly reduce the fluorescence intensity of the underlyingpolymer. These conditions could potentially serve as a referencemeasurement that would be similar to an uncoated patch.

FIG. 6A-6C present data from FTIR scans of flat polymer discs with driedvaccine for the purpose of potentially identifying useful spectralfeatures. FIG. 6A is the spectra obtained from the polymer without driedvaccine. FIGS. 6B and 6C are data from different regions within thedried vaccine drop (edge of dried drop, and center of dried drop).Spectral features in the wavenumber range from 1300 cm-1 to 1900 cm-1are highlighted that seem to correlate with the presence of driedvaccine.

FIG. 7 is a schematic diagram of one embodiment of the equipment setupfor reflectance detection of a coating on a substrate

FIG. 8A is a drawing of one embodiment of the equipment setup fordetecting the coating on a coated substrate; and FIG. 8B is a drawing ofan alternate embodiment of the equipment setup for detecting thecoating.

FIG. 9 is a schematic diagram of one embodiment of the equipment setupfor detecting the coating on a coated substrate.

FIG. 10 is a schematic diagram of one embodiment of the laser diodehousing.

FIG. 11 is a schematic diagram of one embodiment of the receiverhousing.

FIG. 12 is a schematic diagram of one embodiment of the patch mount.

FIG. 13 is a plot of normalized reflectance versus coating transferefficiency.

FIG. 14 is a schematic diagram of one embodiment of the housing of thedevice.

FIG. 15 is a schematic diagram of one embodiment of the device as viewedthrough the housing of the device.

FIG. 16 is a schematic diagram of one embodiment of the device as viewedthrough the top of the housing of the device.

FIG. 17A is a schematic diagram of one embodiment of the device asviewed through the side of the housing of the device; FIG. 17B is aschematic diagram of one embodiment of the device without the housing.

FIG. 18A is a plot of low dose total protein transfer (μg) versus laserreflectance (%); FIG. 19B is a plot of high dose total protein transfer(μg) versus laser reflectance (%).

FIG. 19 is a table of laser acceptance criteria for low dose and highdose amounts.

FIG. 20A is a schematic of the coating percentages by quadrant for amicroprojection array; FIG. 20B is a “heat map” representation ofreflectance vs position data of the coating of the microprojectionarray. Green color represents a high intensity (i.e. Significant tipcoating) and red color is mapped to low intensity readings (i.e. Withsignificant base coating).

FIG. 21A is top-down view of an illustrated example of a patch mat; FIG.21B is a side-view of an illustrated example of a patch mat.

FIG. 22 is a schematic diagram of one embodiment of a quality controlstation where a mat of patches may be coated by multiple print heads andthen conveyed to a quality control station where the patches can bechecked for amount and position of coating on the microprojections.

FIG. 23 is a schematic of one system that provides feedback informationso that the coating of the MAPs performed by the print heads can bemonitored and adjusted based on the data.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to devices and methods for detecting theamount of material coating a medical device or substrate, in particularthe present invention relates to devices and methods for detecting theamount of vaccine material coating a microarray patch in real time.

The patches take a variety of forms from metal formed patches to polymermolded patches to patch projections formed from the vaccine orpharmacological solution itself. The manufacture of these patches relieson the ability to deposit a dried down drug solution or vaccine onto thetips of the microprojections with high throughput and high accuracy.Accurately coating the projections is important as the delivery of thecoated material to the patient needs to be consistent. If too littlematerial is delivered the efficacy of the treatment is compromised. Toomuch material could lead to overdosing or at a minimum wasting expensivevaccine or drug. The ability to coat the patches quickly is necessary toproducing a commercial product. Coating of a Micro Array Patch (MAP) andother vaccine and biologic platforms requires the precise dosing andallocation of biologics targeting each individual projection on theplatform with a controlled dose. Typically, a MAP (Micro Array Patch)platform has a length and a width of less than 20 mm and carries anevenly spaced two-dimensional array of projections. The microprojectionsare situated on a substantially planar base. The number of projectionsin either dimension may be less than 100. Therefore the projectiondensity on the MAP is usually between 2,000 and 10,000 per cm². Thetotal amount of pharmaceutical formulation such as a vaccine required tocoat each projection is typically more than 500 picolitres and must beaccurately measured both in terms of the applied dried volume ofmaterial and the position of the material on the microprojection. Forexample it would be informative to determine whether the materialdeposited on the microprojections was located on the top fourth of themicroprojection or top half of the microprojection or whether the entiremicroprojection was coated. Furthermore, in order to accomplish largevolume manufacturing of MAPs, each patch may need to be coated with oneor more drops (e.g. 1-6 drops per microprojection or between 20 pl to 1μL of material) in in a short time period (e.g. seconds). It isimportant to be able to quantify the amount of material that isdistributed onto the microprojections in a manner that is preferablynon-destructive and which does not contact the material or themicroprojections. The method should be rapid enough to keep up withproduction levels of microprojection arrays which could number in themillions per week. The devices and methods of the present inventionprovide the ability to determine the amount of material coated onto themicroprojections of the MAP.

The devices and methods of the present invention can determine theamount of material deposited on a substrate where the substrate is madeof both an area that is nominally “to be coated” and an area that isnominally “uncoated”. The measurement of the coating distribution can inprinciple be made by the direct measurement of the material on thecoated area of the substrate or inferred by the measurement of theabsence of material in the nominally uncoated area of the substrate. Forexample with respect to microprojection arrays which are made of a basefrom which microprojections arise, the coated area is the tips of themicroprojections (preferably the top half of the microprojections) andthe uncoated area is the base from which the microprojections arise(preferably the lower 50% of the projection). Thus the measurement ofthe material on the microprojections can be made either directly bydetermining the amount of material on the microprojections or by themeasurement of material on the base from which the amount of material onthe microprojections can be determined. The devices and methods of thepresent invention enable the use of electromagnetic radiation directedonto an uncoated/coated microprojection array or micro array patch (MAP)to be reflected off the array or to induce an electromagnetic emissionand detected to determine the extent of coating of the microprojectionson the microprojection arrays. In the devices and methods of the presentinvention the detection of the coating on the MAP may utilize one ormore electromagnetic radiation wavelengths for reflectance measurementsor fluorescence detection. The devices and methods of the presentinvention may use reflectance measurements and fluorescence measurementsalone or in combination either simultaneously or sequentially. Opticsmay be required for reflectance mode measurements to make sureillumination is collimated. Fluorescence mode illumination may notrequire collimated light.

The use of a laser (or other illumination source with appropriateillumination filters), and an intensity sensor (with appropriatelychosen collection filters) to measure the reflected or emitted intensityof the electromagnetic radiation from a coated MAP correlates withcoating performance or transfer efficiency of the coating onto themicroprojections. The sensor may ideally have optics for bothreflectance and fluorescence mode measurements in order to maximizesignal collection and directionality of photons.

In the devices and the methods of the present invention the uncoatedsurfaces of the MAP (e.g. a polymer microprojection array patch) havedifferent reflectance and/or fluorescence emission spectra from apolymer surface that is coated; the orientation of the sensor relativeto the substrate surface being measured can assist in isolating signalsthat are primarily related to coating on either the base region, or thetip region (depending on the sensor configuration); coating on a surfaceis detected as a reduction in the signal intensity compared to thesignal from a reference surface; the reference surface can be anuncoated patch or a measurement made at a wavelength where the coatingis substantially transparent, and is thus representative of an uncoatedpatch. For example, in a reflectance configuration for measuring asignal related to the amount of base coating the illumination source andsensor may be positioned such that if the patch were replaced by amirror, the beam would reflect off the mirror and enter directly inalignment with the sensor optics detection path. When the mirror isreplaced with a microprojection patch, the illumination will, like themirror, substantially reflect off of the base region of the patch.Regions of the patch, where there are microprojections, will notcontribute a significant signal in the direction of the sensor since themicroprojections are substantially orthogonal to the base of the patch.Therefore, the measured signal is primarily from the reflection of theelectromagnetic radiation from the base. However, if a material such asa vaccine is present on the base, the material will act to reduce thereflected signal (either from absorption by the material or byscattering). If the quantity of material deposited onto the patch isknown and controlled, the amount of coating on the tips can then beinferred from the measured quantity on the base. In the case wherematerial is substantially deposited on the tips with little materialdeposited on the base, the measured reflectance intensity signal will behigh (ostensibly the same or similar as an uncoated patch). If materialis instead deposited on the base, the reflected intensity will bereduced. Thus, if a high proportion of tip is coated the result will bethe detector will observe a large signal, whereas a low proportion oftip coating will result in a small signal.

In one embodiment of the devices of the present invention the device iscomprised of a radiation (light) source, a coated microprojection arrayand a sensor for detecting radiation (light). The radiation sourceilluminates the coated array and the sensor is positioned such that itcan detect the radiation reflected from the coated array. To determinethe amount of coating on the microprojection array the value ofreflected light derived from the sensor may be compared to the value ofreflected light derived from the sensor when the same radiation sourceis reflected off an uncoated microprojection array. A normalizedreflectance diagram can be constructed (See FIG. 13) which correlatesthe normalized reflectance of the radiation with the transfer efficiencyof the coating onto the microprojections. Example 1 provides the detailsof the construction of the normalized reflectance diagram, but inessence several different coating amounts may be applied to severaldifferent microprojection arrays such that different transfer efficiencyof the coating is achieved. The transfer can be measured in a variety ofways including a membrane transfer method in which the materialtransferred to the membrane from the microprojections was quantified byusing scintillation counting of 14 C or Ponseau S staining. While theinitial transfer efficiency measurement may be made in a destructivefashion the measurements may be made with methods which arenon-destructive. These different microprojection arrays can then besubjected to irradiation by the radiation source and the reflectedradiation measured by the sensor. An uncoated microprojection array canthen be tested and the normalized reflectance can be calculated bydividing the reflectance values obtained in the various coatedmicroprojection array by the reflectance value obtained from theuncoated array. If all of the coating material is transferred to themicroprojections then none of the material will be on the base of thearray. Thus, the reflectance value of an array where none of thematerial is transferred to the base is the same as that of the uncoatedarray. Reflectance values of the coated array which are less that thereflectance values of the uncoated arrays indicate that some of thecoating material was transferred to the microprojections. Once thecorrelation of the normalized reflectance and the transfer efficiency isestablished then the measurement of the transfer efficiency of anycoated microprojection array can be ascertained. The transfer efficiencyof the coated microprojection array can be determined in anon-destructive, real-time fashion.

As described above the reflectance from the coated patch may be comparedto the reflectance from the uncoated patch. This comparison could beaccomplished by having an uncoated and coated patch illuminatedsimultaneously or sequentially. The comparison could also beaccomplished by comparing a portion of a single patch which containsboth coated and uncoated sections.

In addition to the basic scheme described above other optical equipmentand/or mechanical equipment may also be included in the devices andmethods of the present invention. Various lenses, filters and mirrors tooptimize the illumination of the patch as well as providing optimalconditions for detection of the reflected light may be provided. Ahousing that provides aseptic or sterile conditions for the microarraycan also be part of the devices of the present invention. It isdesirable to maintain an aseptic or sterile environment so that themicroarrays are not contaminated as the coatings on the microprojectionsare to be inserted into patients.

In the devices and methods of the present invention various radiationsources may be used including but not limited to laser sources, infraredsources and fluorescence sources. In some embodiments of the devices andmethods of the present invention the wavelength of the radiation sourcemay be at a wavelength or wavelengths at which the coating stronglyabsorbs. In other embodiments, the dried coating material may eitherstrongly emit fluorescence in response to the excitation wavelength, orstrongly absorb or scatter at the emitted fluorescence wavelength of theunderlying polymer substrate. The direction of the illumination sourceand the detector patch may influence the quality and informationreceived, especially for detection based on reflectance. the orientationof the sensor relative to the microprojection array surface beingmeasured can assist in isolating signals that are primarily related tocoating on either the base region, or the tip region (depending on thesensor configuration). Illuminating near normal to patch surface resultsin a signal that is almost entirely due to the base reflectance(reflections from projections do not return to the sensor). Reflectanceis reduced when coating is present, due to either absorbance by thecoating, or scattering from the dried solids deposits. Placing thesensor at an angle such that tips of other projections in the array maskor shadow the base portion of the projections as well as the base of thepatch coating on a surface is detected as a reduction (or increase insome cases) in the signal intensity compared to the signal from areference surface. Illumination should be electromagnetic radiationsource with a defined wavelength (or wavelengths if 2 or more areneeded)

The orientation of the electromagnetic radiation source and the sensorsinfluence the reflectance signal that registers with the detectors. Forexample, if the detector and illumination source are oriented as in FIG.1A, the tips of the microprojections are visible, but they contributelittle reflectance signal because the light from the tips is notdirected towards the sensor. The reflectance signal intensity is relatedto the light reflected from the base and if the coating material iscoating the base rather than the tips of the microprojections the signalis reduced. FIG. 1B shows the view that a sensor placed in theorientation in FIG. 1A would “see”. For example, FIG. 2C shows the viewthe detector “sees” if the detector is placed in the direction as shownin FIG. 2B and at the angle as shown in FIG. 2A. The tip of themicroprojection is visible while the body of each microprojection ismasked by the adjacent microprojections. However in this case, the baseis also visible between the rows of microprojections. Thus the signalreceived will be a combination of signals emanating from the base andthe top half of each projection. FIG. 2F shows the view the detector“sees” if the detector is placed in the direction as shown in FIG. 2Aand the angle as shown in FIG. 2E. In this case, the tip of themicroprojection is visible and the body of each microprojection ismasked by the adjacent microprojections. Importantly, the base is alsomasked by adjacent microprojections. The received signal comes primarilyfrom the projection tips, but only from the side of the projectionfacing the detector. In order to maximize information collection fromthe entire tip surface, an alternate configuration may be used as inFIG. 3, where the illumination is such that the use of four detectors atapproximately 45 degree downward angle to the microprojections and at 45degrees out of alignment with the rows of microprojections provides asignal primarily from the tips of the microprojection arrays. The use ofthis geometric masking by having the detector detect signals from theupper coated portion of the microprojection rather than from the loweruncoated portion of the microprojection and uncoated base can isolatethe signal from the coated portion of the microprojection.

The size of the area illuminating the substrate, such as amicroprojection array will also influence the quality of the data. Forexample if the area of illumination is a large area relative to theentirety of the substrate the information gathered from the reflectancedata will relate to an average coating over the entire substrate.Smaller areas of illumination relative to the entirety of the substratewill provide more data about the coating of particular areas of thesubstrate. The smaller the area of illumination the greater the detailof the coating on the substrate. For example more detail will be gainedby illuminating a single microprojection than illuminating the entiremicroprojection array. FIG. 4 shows various configurations ofilluminating a microprojection array. With respect to illumination of amicroprojection array the diameter of the illuminating spot can be aslarge as the diameter of the entire array or as small as an individualmicroprojection. In some embodiments the diameter of the illuminationspot may be 10 mm or less or 9 mm or less or 8 mm or less or 7 mm orless or 6 mm or less or 5 mm or less or 4 mm or less or 3 mm or less or2 mm or less or 1 mm or less or 0.5 mm or less or 0.1 mm or less or 0.05mm or less or 0.01 mm or less.

Alternatively the use of fluorescence rather than reflectance maydecrease the dependence of the signal on the geometry of the radiationsource and the detectors as fluorescence emits in all directions. In thecase of reflectance the signal may be reduced by as much as 95% if thesource of the radiation is normal to the patch. Conversely, if thesource of radiation is normal to the patch when using fluorescencedetection, the signal is only marginally reduced. If a coating is coatedonto a substrate such as on the microprojections of a microprojectionarray the wavelength for excitation and the wavelength range for anemission filter can provide scenarios where the coating such as avaccine may either mask the fluorescence of the patch (polymer) orprovide little or no masking of the fluorescence of the patch (polymer).For example, in FIG. 5A, the excitation wavelength is set at 445 nm andthe emission filter is 455-530 nm. In this case the vaccine coating onthe polymer patch masks the fluorescence signal from the polymer therebyreducing the signal. In FIG. 5B, the excitation wavelength is set at 405nm and the emission filter is 495-515 nm. In this case the vaccinecoating on the polymer patch does not mask the fluorescence signal fromthe polymer and only reduces the signal marginally. This signal couldthus potentially serve as a reference signal on a coated patch whichmight enhance the quality of the measurement and/or remove the need tomeasure the patch before it is coated.

The use of Fourier Transform Infrared Spectroscopy (FTIR) may be used toassist in identifying optimal wavelengths for detection of the coatingon a substrate. To achieve maximum sensitivity, it may be desirable toselect a wavelength where the dried vaccine absorbs strongly compared tothe polymer (See FIG. 6). FTIR Spectral Imaging may assist inidentifying strong absorbance peaks that are unique to the driedvaccine.

FIG. 7 is a schematic diagram of a device for measuring reflectance inwhich radiation is projected onto the patch and a receiver detects thereflected light which is communicated to a display device. The radiationsource can be any source that emits radiation. Laser diodes arepreferred as the radiation source as they have high intensity, narrowbandwidth, and are collimated, which simplifies the optical setup. Inone embodiment the laser diode may be a 4.5 mW laser diode that emitslight at 635 nm and has adjustable focus. The laser may be powered by apower supply such as a 5 VDC power supply. A large range of wavelengthsmay be used in the methods and the devices of the present invention. Awavelength between 200 nm to 10 μm may be used for illuminating themicroprojection array. Wavelengths between 200 nm to 10000 nm or between200 nm to 9000 nm or between 200 nm to 8000 nm or between 200 nm to 7000nm or between 200 nm to 6000 nm or between 200 nm to 5000 nm or between200 nm to 4000 nm or between 200 nm to 3000 nm or between 200 nm to 2000nm or between 200 nm to 1000 nm or between 200 nm to 900 nm or between200 nm to 800 nm or between 200 nm to 700 nm or between 200 nm to 600 nmor between 200 nm to 500 nm or between 200 nm to 400 nm or between 200nm to 300 nm or between 300 nm to 10000 nm or between 300 nm to 9000 nmor between 300 nm to 8000 nm or between 300 nm to 7000 nm or between 300nm to 6000 nm or between 300 nm to 5000 nm or between 300 nm to 4000 nmor between 300 nm to 3000 nm or between 300 nm to 2000 nm or between 300nm to 1000 nm or between 300 nm to 900 nm or between 300 nm to 800 nm orbetween 300 nm to 700 nm or between 300 nm to 600 nm or between 300 nmto 500 nm or between 300 nm to 400 nm or between 400 nm to 10000 nm orbetween 400 nm to 9000 nm or between 400 nm to 8000 nm or between 400 nmto 7000 nm or between 400 nm to 6000 nm or between 400 nm to 5000 nm orbetween 400 nm to 4000 nm or between 400 nm to 3000 nm or between 400 nmto 2000 nm or between 400 nm to 1000 nm or between 400 nm to 900 nm orbetween 400 nm to 800 nm or between 400 nm to 700 nm or between 400 nmto 600 nm or between 400 nm to 500 nm or between 300 nm to 400 nm orbetween 500 nm to 10000 nm or between 500 nm to 9000 nm or between 500nm to 8000 nm or between 500 nm to 7000 nm or between 500 nm to 6000 nmor between 500 nm to 5000 nm or between 500 nm to 4000 nm or between 500nm to 3000 nm or between 500 nm to 2000 nm or between 500 nm to 1000 nmor between 500 nm to 900 nm or between 500 nm to 800 nm or between 500nm to 700 nm or between 500 nm to 600 nm or between 600 nm to 10000 nmor between 600 nm to 9000 nm or between 600 nm to 8000 nm or between 600nm to 7000 nm or between 600 nm to 6000 nm or between 600 nm to 5000 nmor between 600 nm to 4000 nm or between 600 nm to 3000 nm or between 600nm to 2000 nm or between 600 nm to 1000 nm or between 600 nm to 900 nmor between 600 nm to 800 nm or between 700 nm to 10000 nm or between 700nm to 9000 nm or between 700 nm to 8000 nm or between 700 nm to 7000 nmor between 700 nm to 6000 nm or between 700 nm to 5000 nm or between 700nm to 4000 nm or between 700 nm to 3000 nm or between 700 nm to 2000 nmor between 700 nm to 1000 nm or between 700 nm to 900 nm or between 700nm to 800 nm. In certain embodiments of the radiation sources used inthe devices and methods of the present invention, 635 nm was utilizedprimarily to reduce the effect of background light (noise) from theroom. At 635 nm the intensity of room lighting at this wavelength isvery low compared to the laser intensity. Filters may be placed in frontof the sensor to significantly remove the other wavelengths of light(primarily from room lighting) from striking the sensor. In certainembodiments the measured signal from the room lights was not detectableby the sensor which measures into the 100 picoWatt range (1010 Watts).The signals from the laser are usually in the microwatt range (106),meaning that the signal detected by the sensor is about 1,000 to 10,000times more intense than the background radiation.

The sensor can be a detector such as a photodiode including but notlimited to silicon photodiodes preferably with a wavelength range400-1100 nm, power range 500 pW-500 mW and coated with an ND reflectivecoating. Placing a filter in front of the sensor can be used to reducestray signals from light coming from the production environment. Afilter can filter out the excitation wavelength when a fluorescencesignal is being measured. Additionally, optical elements placed in frontof the sensor may assist is maximizing the specificity in directionalityand signal amplitude. The sensor can be directly read by a power meterconsole which is compatible with the receiver or a PLC system whichreads the power sensor measurements, processes them, and feeds theinformation into the production system.

FIGS. 8A and 8B and FIG. 9 are schematic diagrams of alternativeembodiments of the present invention that include the components in FIG.7 but in addition may provide various lenses, filters and mirrors tooptimize the illumination of the patch as well as providing optimalconditions for detection of the reflected light. In general lenses canbe convex/convex lenses with 350-700 nm wavelength. The lenses aretypically uncoated. Bi-convex lenses are useful for many finite imagingapplications. This type of lens is best suited for use in situationswhere the object and image are on opposite sides of the lens and theratio of the image and object distances (conjugate ratio) is between 0.2and 5. Filters include bandpass filters which provide one of thesimplest ways to transmit a well-defined wavelength band of light, whilerejecting other unwanted radiation. Their design is essentially that ofa thin film Fabry-Perot Interferometer formed by vacuum depositiontechniques and consists of two reflecting stacks, separated by aneven-order spacer layer. These reflecting stacks are constructed fromalternating layers of high and low refractive index materials, which canhave a reflectance in excess of 99.99%. By varying the thickness of thespacer layer and/or the number of reflecting layers, the centralwavelength and bandwidth of the filter can be altered. In one particularembodiment the filter permits transmission of 635±2 nm. The design alsomay include the use of mirrors such as broadband dielectric mirror400-750 nm.

FIG. 10 is a schematic diagram of one embodiment of the laser diodehousing of the devices and methods of the present invention. The designof the laser diode housing includes a laser diode housing, laser diode,an aspheric lens, a beam shaping diffuser and a focusing lens. Theaspheric lens will cause the beam coming from the laser diode to divergeand the beam shaping diffuser will shape the beam. After passing throughthe beam shaping diffuser the focusing lens will focus the shaped beamonto the patch. Optionally a diaphragm may be placed between thefocusing lens and the patch.

FIG. 11 is a schematic diagram of one embodiment of the receiver housingof the devices and methods of the present invention. The design of thereceiver housing includes a receiver housing a biconvex lens and areceiver. The biconvex lens causes the reflected light to converge atthe receiver.

FIG. 12 is a schematic diagram of one embodiment of the patch mount ofthe devices and methods of the present invention where the patch isdisplayed on or in a patch housing. The patch housing serves to hold thepatch in place during the illumination of the patch. The area ofillumination of the patch may be the entire patch or alternatively someportion of the patch.

FIGS. 14-17 are schematic diagrams of different aspects of oneembodiment of the devices of the present invention.

Optionally a reference sensor as shown in FIGS. 8A and 8B can beincorporated into the design as a reference sensor may provide extrainformation such as a signal that is due to scattering rather thanreflected light. Additionally the reference sensor might provide areference signal that is essentially a surrogate measure of the incidentlaser intensity. This would potentially help stabilize the readings overtime if the laser intensity drifts, or the optics setup shifts over timeor deteriorates and or provide the ability to replicate results fromsystem to system.

In one embodiment the signals from the sensor are normalized bymeasuring a blank (uncoated) patch prior to or simultaneously withmeasuring the signal for coated patches. The ratio of the coated patchsignal to the uncoated patch signal may then be calculated.

As shown in FIG. 7, in one embodiment of the devices and methods of thepresent invention the radiation source is placed at an angle from themicroarray patch such that the incident radiation hits the patch atangle where the light is reflected at an angle and detected by thesensor. As shown in FIG. 8A the angle of incidence of the radiationsource with respect to the patch is 8°. FIG. 8B shows an alternativeembodiment where the radiation source is normal to the patch.

It is also possible to illuminate at an angle such that using thegeometry of the patch a shadow could be cast on the lower part of theprojection and leave a signal that is primarily from the tips of themicroprojections rather than from the base.

In alternative embodiments of the present invention a “spectral”measurement may be taken in which multiple wavelengths are monitored forintensity spectra which may be signatures of different components in thecoating or the polymer patch.

As described above, the instruments, devices and methods of the presentinvention need to provide high throughput quality solutions fordetermining the coating on the microprojection arrays. This includeshaving the patches that will be coated in a format where they can becoated, checked for quality and transported easily. A method forproviding patches that can be coated by commercial production is tointerconnect the individual MAP's into compact mats that can be furtherstacked into a single compact body that requires minimal packaging(FIGS. 21A and 21B). The mats can be individually manipulated in anaseptic environment. The mat of patches can be coated as one unitthereby minimizing the instrument footprint. The patch mats providein-plane cohesion of the patches, while allowing slight individualfreedom of movement of the patch out of plane which enables each patchto be perfectly mated to the coating base. The patches can beindividually detached from the mat by a pick-and-place robot. Thepatches of the patch mat may be coated using print head designs thatutilize a piezoelectric stack actuator as the driving component to pusha membrane plate such that the fluid in the pumping chamber is dispensedthough a two-dimensional array of nozzles. The dispensed fluid is coatedonto microprojections on a microprojection array as the nozzles arealigned with the microprojections on the array. The print head functionsin the following way. The print head has a source of fluid from areservoir which may be integral or externally located. Initially, thefluid from the reservoir to the nozzle is at a static condition, i.e.,no flow. Between the reservoir and the nozzle, there are microfluidicconduits and a pumping chamber. The microfluidic conduits areresponsible for replenishing fluid from the reservoir to the pumpingchamber. The pumping chamber is responsible for pumping fluid out fromthe nozzle. At the nozzle exit, there is a meniscus or liquid/airinterface defined by the nozzle exit geometry, which is some embodimentsforms a round meniscus. The print head device may provide that each dropejection cycle enable all the nozzles to simultaneously dispense a dropor a sequence of drops with a total volume in the range of 30 to 3000picoLiters per nozzle. The print head may provide that each dropejection cycle enable a single nozzle or subset of nozzles to dispense adrop or a sequence of drops.

FIG. 22 shows one scheme by which the patches on the patch mat arecoated by a printer and transferred to a conveyer where the patches maybe tested for quality by the devices and methods of the presentinvention.

The sequence begins with the system start up for each print head inwhich a start priming sequence is initiated to expel air from the printcircuit. Once primed, printer will idle (tickle). The print head willprint a single dispense onto a hydrophobic surface, image system countsdrops, measures drop diameter and aligns print head to X,Y, axis androtation. Drop size can be adjusted via PZT voltage.

Next an array of patches (Mat) is aligned under the print head, eachpatch is imaged and the position of the patch relative to axis isdetermined. Print head vision systems (P1 to P4) inspect patches andmark rejects (missing projections, no tips or damage). In additionperiodic checks of drop mass dispense can be performed to confirm targetdispense. The voltage supplied to PZT may be altered to achieve the meandispensing value. Printing can then commence and a coating is built upon the microprojections by multiple passes depending on required dose.The printed mat of patches is then transferred to coating QC conveyor.

The mat patch passes under QC station and reflected light of variouswavelengths may be used to collect data per patch. Such data may includewhere the coating is positioned on projection and estimates of thedispensed mass per patch. Mass may be calculated by reading fluorescenceemitted from one component of a homogeneous coating material or thepatch itself. This data from the fluorescence scan may be checkedagainst the dispensed mass check for that print head to confirm the anydeviations from the established protocol. Any out of specificationpatches are rejected at the patch insertion stage.

FIG. 23 is a schematic of one system that provides feedback informationso that the coating of the MAPs performed by the print heads can bemonitored and adjusted based on the data. The system is designed torespond to out of specification data by purging the print head andprinting a single array to check drop size as well as clearing nozzlesand adjusting position. PZT voltage can be adjusted to increase ordecrease dispensed mass. If the position of the coating moves from atarget value for a particular print head that print head will be askedto perform a calibration check.

In view of the above, it will be appreciated that a method forcontrolling the quality of coated microprojection arrays may includedetermining the amount of coating on microprojections of a coatedmicroprojection array using the above described techniques, comparingthe determined amount of coating to a coating specification; andrejecting the coated microprojection array if the determined amount ofcoating is outside of the coating specification.

Similarly, it will be appreciated that a system for controlling thequality of coated microprojection arrays may include a device thatdetermines the amount of coating on microprojections of a coatedmicroprojection array as described above, together with a processingsystem configured to receive from the device an indication of thedetermined amount of coating, compare the determined amount of coatingto a coating specification and determine that the coated microprojectionarray should be rejected if the determined amount of coating is outsideof the coating specification.

Within this disclosure, any indication that a feature is optional isintended provide adequate support (e.g., under 35 U.S.C. 112 or Art. 83and 84 of EPC) for claims that include closed or exclusive or negativelanguage with reference to the optional feature. Exclusive languagespecifically excludes the particular recited feature from including anyadditional subject matter. For example, if it is indicated that A can bedrug X, such language is intended to provide support for a claim thatexplicitly specifies that A consists of X alone, or that A does notinclude any other drugs besides X. “Negative” language explicitlyexcludes the optional feature itself from the scope of the claims. Forexample, if it is indicated that element A can include X, such languageis intended to provide support for a claim that explicitly specifiesthat A does not include X. Non-limiting examples of exclusive ornegative terms include “only,” “solely,” “consisting of,” “consistingessentially of,” “alone,” “without”, “in the absence of (e.g., otheritems of the same type, structure and/or function)” “excluding,” “notincluding”, “not”, “cannot,” or any combination and/or variation of suchlanguage.

Similarly, referents such as “a,” “an,” “said,” or “the,” are intendedto support both single and/or plural occurrences unless the contextindicates otherwise. For example “a dog” is intended to include supportfor one dog, no more than one dog, at least one dog, a plurality ofdogs, etc. Non-limiting examples of qualifying terms that indicatesingularity include “a single”, “one,” “alone”, “only one,” “not morethan one”, etc. Non-limiting examples of qualifying terms that indicate(potential or actual) plurality include “at least one,” “one or more,”“more than one,” “two or more,” “a multiplicity,” “a plurality,” “anycombination of,” “any permutation of,” “any one or more of,” etc. Claimsor descriptions that include “or” between one or more members of a groupare considered satisfied if one, more than one, or all of the groupmembers are present in, employed in, or otherwise relevant to a givenproduct or process unless indicated to the contrary or otherwise evidentfrom the context.

Where ranges are given herein, the endpoints are included. Furthermore,it is to be understood that unless otherwise indicated or otherwiseevident from the context and understanding of one of ordinary skill inthe art, values that are expressed as ranges can assume any specificvalue or subrange within the stated ranges in different embodiments ofthe invention, to the tenth of the unit of the lower limit of the range,unless the context clearly dictates otherwise.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference. The citation of any publication is for its disclosure priorto the filing date and should not be construed as an admission that thepresent invention is not entitled to antedate such publication by virtueof prior invention.

Throughout this specification and claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” or “comprising”, will be understood to imply the inclusionof a stated integer or group of integers or steps but not the exclusionof any other integer or group of integers. As used herein and unlessotherwise stated, the term “approximately” means ±20%.

While this invention has been particularly shown and described withreferences to example embodiments thereof, it will be understood bythose skilled in the art that the various changes in form and detailsmay be made therein without departing from the scope of the inventionencompassed by the appended claims.

A better understanding of the present invention and of its manyadvantages will be had from the following examples, given by way ofillustration.

EXAMPLES Example 1 Normalized Reflectance

A range of coating performance was obtained by creating three differentgroups of microprojection patch arrays. Each patch was coated with 6drops of 14 C labelled vaccine per projection. The three groups werethen manufactured as follows: In group I six drops were targeted to thetips of the microprojections; in group II, three drops were targeted totips of the microprojections and three drops targeted to the base; andin group III, six drops were targeted to the base and no drops targetedto the micro projections. Multiple replicates of each group weremanufactured. As the process for targeting the drops to particularportions of the array cannot as yet be perfectly replicated there was aspread of coating performance instead of simply three clusters at 0%,50% and 100% coating. These microprojection arrays were made induplicate (TN821 and TN 848). Both sets of microarrays were subjected toreflectance measurements as were microarrays which were uncoated.

The quantitation of the coating for a first set (TN 821) of microarrayswas measured by a membrane transfer method where a porous 100 micronthick membrane is used to remove the coated material from the top 100microns of the projections. The membrane (PVDF with 0.4 micron pores)was hydrated with ¼ strength phosphate buffer and placed against a rigidsurface (e.g. glass slides). The patch was placed with the projectionside facing the membrane and a pneumatic press was used to press theprojections into the membrane for 5 seconds at 40 PSI. Projectionspenetrate the membrane and stop when the microprojection tips reach theglass surface. Thus, the thickness of the membrane and the pressure (tosome extent) control the penetration of the microprojections into themembrane. The coating transfers to the membrane where it was retaineddue to the hydrophobic interactions between the coating and themembrane. The membrane is hydrated and is a high protein bindingmembrane traditionally used in blotting techniques for protein analysis.The remaining material (that was not transferred to the membrane) waseluted from the patch and the material bound to the membrane wasquantified by using scintillation counting.

The results of the reflectance studies are show in FIG. 13. The redsquares correspond to TN 821 in which the reflectance was measured andnormalized to a microarray having no coating and then the microarrayswere subjected to membrane transfer. The green squares correspond to TN848 821 in which only the reflectance was measured and compared to thevalues generated for TN 821. The plot demonstrates that the reflectancemethods of the present invention may be used to quantitate the transferof coating to microprojections.

Example 2 Large Spot Reflectance

Eight MAPs were coated respectively with the following coatings: 30%,60%, 80% and 100% high dose coating and 30%, 60%, 80% and 100% low dosecoating. A laser source illuminated a 7 mm spot on the microprojectionarray and reflectance was measured. The amount of coating was plottedversus reflectance as seen in FIGS. 18A and 18B. A Laser AcceptanceThreshold can be established by calculating a “mean+4×standarddeviation” (99.993% confidence interval) by bracketing the coatingtransfer specification limits which can be determined by the type ofdevice used to coat the substrate and the amount of coating required fora particular purpose. In this example doses 5 and 7 were selected forthe lower end and 6 and 8 were selected for the higher end. FIG. 19shows a table of the acceptance calculations.

Example 3 Spatially Resolved QC Measurements

A single MAP was coated with 4 different tip targeting accuracies asshown in FIG. 20A with one quadrant with 100% tip coating, a secondquadrant with 66.7% tip coating, a third quadrant with 33.3% tipcoating, and a fourth quadrant with 0% tip coating. “Point-scan” Laserbeam (˜1 mm Dia.) scanned throughout patch and corresponding Laserreflectance measurements were made. The loss in laser reflectance isplotted in heat map as shown in FIG. 20B. Point-scan measurements areused to distinguish spatial coating variations within a single patch.

1) A method for determining the amount of coating on microprojections ofa coated microprojection array, the method comprising: a) irradiating anuncoated microprojection array with an electromagnetic radiation source;b) measuring the reflected radiation from the uncoated microprojectionarray; c) irradiating a coated microprojection array with anelectromagnetic radiation source; d) measuring the reflected radiationfrom the coated microprojection array; and e) determining the amount ofcoating on the microprojections by comparing the reflected radiationfrom the uncoated microprojection array to that of the coatedmicroprojection array. 2) The method of claim 1, wherein the measuringof the reflected radiation from the uncoated microprojection array andthe measuring of the reflected radiation from the coated microprojectionarray is done simultaneously. 3) The method of claim 1 or claim 2,wherein the measuring of the reflected radiation from the uncoatedmicroprojection array and the measuring of the reflected radiation fromthe coated microprojection array is done sequentially. 4) A method fordetermining the amount of coating on microprojections of a coatedmicroprojection array, the microprojection array comprising a base fromwhich the microprojections project, the method comprising: a)irradiating the coated microprojection array with a light source; b)measuring the reflected radiation from the base of the coatedmicroprojection array; and c) determining the amount of coating on themicroprojections by comparing the reflected radiation from the coatedmicroprojection array to that of an uncoated microprojection array. 5)The method of claim 4, wherein the reflected radiation is measured by asensor. 6) The method of claim 5, wherein the number of sensors is four.7) The method of claim 6, wherein the sensors are at approximately 45degree downward angle to the microprojections and at 45 degrees out ofalignment with the rows of microprojections. 8) The method of claim 7,wherein the electromagnetic radiation source is substantiallyperpendicular to the microprojection array. 9) The method of claim 7,wherein the electromagnetic radiation source is at an angle relative tothe microprojection array. 10) The method of claim 7, wherein theelectromagnetic radiation source is aligned over the microprojectionarray such that the angle relative to the microprojections is less than5°. 11) The method of claim 7, wherein the electromagnetic radiationsource is aligned over the microprojection array such that the anglerelative to the microprojections is less than about 20°. 12) The methodof claim 7, wherein the electromagnetic radiation source is aligned overthe microprojection array such that the angle relative to themicroprojections is less than about 45°. 13) A device for measuring thecoating on the microprojections on a microprojection array comprising:a) an electromagnetic radiation source for illuminating themicroprojection array; b) a microprojection array housing for mountingthe microprojection array; and c) one or more sensors for detectingreflected or emitted radiation from the microprojection array. 14) Thedevice of claim 10, wherein the radiation source is a laser diode. 15)The device of claim 11, wherein the radiation source is a laser diodewhich emits radiation from about 200 nm to 10000 nm. 16) The device ofclaim 12, wherein the radiation source is a laser diode which emitsradiation at 635 nm. 17) The device of claim any one of claims 10 to 13,wherein the sensor is a silicon photodiode. 18) The device of claim 14,wherein the silicon photodiode has a detection range of 200 to 1100 nm.19) The device of any one of claims 10 to 15, wherein the device isconfined in an aseptic housing. 20) The device of any one of claims 10to 16, further comprising a reference sensor. 21) The device of any oneof claims 10, wherein the number of sensors is four. 22) The device ofclaim 18, wherein the sensors are at approximately 45 degree downwardangle to the microprojections and at 45 degrees out of alignment withthe rows of microprojections. 23) The device of claim 19, wherein theelectromagnetic radiation source is substantially perpendicular to themicroprojection array. 24) The device of claim 19, wherein theelectromagnetic radiation source is aligned over the microprojectionarray such that the angle relative to the microprojections is less than5°. 25) A device for measuring the coating on the microprojections on amicroprojection array, the device comprising: a) a laser diode forilluminating the microprojection array; b) an aspheric lens; c) a beamshaping diffuser; d) a focusing lens wherein the aspheric lens ispositioned between the laser diode and the beam shaping diffuser and thebeam shaping diffuser is positioned between the aspheric lens and thefocusing lens and the focusing lens is positioned between the beamshaping filter and the microprojection array housing; e) amicroprojection array housing for mounting a microprojection array; f) abi-convex lens; g) one or more sensors for detecting reflected lightfrom the microprojection array, wherein the biconvex lens is positionedbetween the microprojection array housing and the receiver; and h) apower meter connected to the sensor. 26) The device of claim 22, furthercomprising a microarray mounting station. 27) The device of claim 23,further comprising one or more microarrays. 28) The device of any one ofclaims 22 to 24, wherein the laser diode emits electromagnetic radiationat bout 635 nm. 29) The device of any one of claims 22 to 25, furthercomprising an aperture positioned between the focusing lens and themicroprojection array housing. 30) The device of any one of claims 22 to26, further comprising a mirror positioned between the aperture and themicroprojection array housing 31) The device of any one of claims 22 to27, further comprising a reference sensor. 32) The device of any one ofclaims 22 to 28, wherein the number of sensors is four. 33) The deviceof any one of claims 22 to 29, wherein the sensors are at approximately45 degree downward angle to the microprojections and at 45 degrees outof alignment with the rows of microprojections. 34) The device of claim30, wherein the laser diode is substantially perpendicular to themicroprojection array. 35) The device of claim 30, wherein the laserdiode is aligned over the microprojection array such that the anglerelative to the microprojections is less than 5°. 36) A method fordetermining the extent (degree, amount) of coating on microprojectionsof a coated microprojection array comprising: a) irradiating an uncoatedmicroprojection array with an electromagnetic radiation source; b)measuring the emitted radiation from the uncoated microprojection array;c) irradiating a coated microprojection array with a light source; d)measuring the emitted radiation from the coated microprojection array;and e) determining the extent of coating on the microprojections bycomparing the emitted radiation from the uncoated microprojection arrayto that of the coated microprojection array. 37) The method of claim 33,wherein the emitted radiation is fluorescence. 38) The method of claim33 or claim 34, wherein the electromagnetic radiation source emits atapproximately 445nm. 39) The method of claim 34, wherein thefluorescence is detected by a sensor with a filter having a bandpass ofbetween about 455 nm to 515 nm. 40) A method for determining the extent(degree, amount) of coating on a substrate comprising: a) irradiating anuncoated microprojection array with a first electromagnetic radiationsource which reflects off the substrate and a second electromagneticradiation source which promotes fluorescence in either the substrate orthe coating or both; b) measuring the reflected radiation from theuncoated microprojection array; c) measuring the emitted fluorescenceradiation from the uncoated microprojection array; d) irradiating acoated microprojection array with a first electromagnetic radiationsource which reflects off the substrate and a second electromagneticradiation source which promotes fluorescence in either the substrate orthe coating or both irradiating a coated microprojection array with alight source; e) measuring the reflected radiation from the coatedmicroprojection array; f) measuring the emitted fluorescence radiationfrom the coated microprojection array; and g) determining the extent ofcoating on the microprojections by comparing the reflected radiationfrom the uncoated microprojection array to that of the coatedmicroprojection array and by comparing the reflected radiation from theuncoated microprojection array to that of the coated microprojectionarray. 41) A method for controlling the quality of coatedmicroprojection arrays, the method including: a) determining the amountof coating on microprojections of a coated microprojection array usingthe method of any one of claims 1 to 9; b) comparing the determinedamount of coating to a coating specification; and c) rejecting thecoated microprojection array if the determined amount of coating isoutside of the coating specification. 42) A method for controlling thequality of coated microprojection arrays, the method including: a)determining the extent of coating on microprojections of a coatedmicroprojection array using the method of any one of claims 33 to 39; b)comparing the determined extent of coating to a coating specification;and c) rejecting the coated microprojection array if the determinedamount of coating is outside of the coating specification. 43) A systemfor controlling the quality of coated microprojection arrays, the systemincluding: a) a device according to any one of claims 10 to 32 thatdetermines the amount of coating on microprojections of a coatedmicroprojection array; and b) a processing system configured to: i)receive, from the device, an indication of the determined amount ofcoating; ii) compare the determined amount of coating to a coatingspecification; and iii) determine that the coated microprojection arrayshould be rejected if the determined amount of coating is outside of thecoating specification.